Fig. 8: Proposed mechanisms of the D1–D2DR heteromer-mediated signaling pathway in neuropathic pain.

Activation of the D1–D2DR heteromer leads to intracellular calcium mobilization from IP3 receptor-sensitive stores through a cascade of events involving rapid translocation of Gαq to the plasma membrane and activation of PLC. The increase in the calcium concentration leads to the promotion of PKC γ, CaMKII, MAPK, and CREB activation, which could increase the excitability of spinal neurons to promote the development of chronic neuropathic pain. l-CDL inhibits the formation of the D1–D2DR complex and downstream PKC γ, CaMKII, MAPK, and CREB signaling to alleviate CCI-induced neuropathic pain.